The envelope glycoproteins, gp120 and gp41, of HIV (HTLV- 3/LAV) are critical components of the infectious virus, that through specific interactions with the T4 molecule on the surface of helper T lymphocytes mediate the attachment and entry of the virus. In addition, the envelope glycoprotein/T4 interaction can result in cell to cell fusion and loss of cell viability. The high specificity of target cell recognition and depletion of the T-helper subclass of lymphocytes is at least partly responsible for the immune disfunction observed in patients suffering from AIDS. In an attempt to better understand the structure of the HIV env gene product, we are proposing to define the topology of the HIV envelope glycoprotein complex through biochemical and molecular genetic approaches; to establish the organization and functional role of the long cytoplasmic domain of gp41 by construction of mutant env genes and their expression in an SV40 vector system; to engineer and express at high levels an uncleaved, secreted variant env gene product that con be obtained in sufficient amounts and purity for crystallization; to determine the 3- dimensional structure of the soluble HIV glycoprotein complex and those of the related retroviruses (STLV-3, HTLV-4); and to utilize this information for the design of antagonistic blockading reagents that might prevent gp120 binding to the T4 receptor.